Method of treating hypercholesterolemia with candimycin

ABSTRACT

Orally administered compositions for altering lipid metabolism are described herein, these compositions containing an effective dose of candimycin. Also the method of altering lipid metabolism including reducing and controlling the blood cholesterol level, is described herein.

This is a division of Ser. No. co-pending application 521,289 filed Nov.6, 1974, now U.S. Pat. No. 4,039,659 which is a division of Ser. No.177,512 filed Sept. 2, 1971, now U.S. Pat. No. 3,855,409 which is acontinuation of Ser. No. 221,062 filed Jan. 26, 1972, now U.S. Pat. No3,966,910 and a continuation of Ser. No. 24,797 filed Apr. 1, 1970(abandoned) which is a continuation of Ser. No. 627,313 filed Mar. 31,1967, now U.S. Pat. No. 3,627,879.

This invention relates to a composition containing a polyenic macrolidecompound and the method of altering lipid metabolism by orallyadministering the same.

The implication of the blood lipids as a contributing factor in thefunctioning of the highly vascularized organs such as the kidneys,liver, brain, lungs, testes, heart, and other organs requiring smooth,free, sufficient blood flow has contributed to the intensive andvigorous research for agents, that will control the lipid content,including triglycerides, cholesterol, lipoproteins, etc., in the bloodstream and tissues. A majority of studies have focused on cholesterolbecause of the substantial evidence available relating blood cholesterollevels to conditions such as atherosclerosis, arteriosclerosis and otherschlerotic conditions, coronary heart disease, cerebral hemorrhage,liver and kidney dysfunction associated with vascular obstruction,sterol calculi resulting for hypercholesterolemia, etc.

Diseases such as arteriosclerosis, which is a generic term for a numberof chronic pathologic conditions, affect the intima or the media ofarteries and is characterized by thickening, hardening and loss ofelasticity of vessel wall with resultant alteration in size of thelumen. Atherosclerosis, which is a form of arteriosclerosischaracterized by intimal thickening due to localized accumulations oflipids, known as atheromas. Atherosclerosis is of great importancebecause of its predilection for coronary (cerebral) and peripheralarteries. It develops insidiously, probably due to multiple factors(metabolic, humoral and hemodynamic being of primary significance).

The earliest lesions of atherosclerosis are the subintimal fatty streaksseen in the thoracic aorta in young mammals, which either retrogress orgrow larger, forming plaques. While these may involve any artery, theyare most common in the aorta, coronary, cerebral, and peripheralarteries of the lower extremities. Subintimal hemorrhage or ulcerationof the plaque may lead to thrombosis and occlusion of the involvedvessel, resulting in a variety of symptoms and signs due to ischemia.

It is believed that B-lipoproteins are basically responsible for thedisease process. These lipoproteins are a heterogeneous family ofmacromolecules containing protein, cholesterol, phospholipids andtriglycerides in varying proportions. The chemical measurement of any ofthese lipids is an index of the accumulation of lipoproteins of a givendensity. These lipoproteins, which are essential but not solelysufficient to cause disease, interact with the arterial wall in such away as to produce the discrete intimal lesion.

The most frequent and important cause of acute renal failures(dysfunction) is acute tubular necrosis (lower nephron nephrosis orkidney shutdown). Although the causes advanced for this condition arenumerous it is postulated that lipoid material depositing on thecapillary walls may also contribute. Functional renal disorders are alsoassociated with arteriolar nephrosclerosis which consists of sclerosisof the small renal arterioles. There is also interference with thenormal function of the kidney in cases of atherosclerosis in which thereis a thickening of the peripheral arteries due to localizedaccumulations of lipids known as atheromas.

Liver dysfunction associated with vascular obstruction is often seen inobese mammals in whom it is due to excessive fat intake. Fattyinfiltration of the liver can also be caused by numerous factorsincluding chronic infections (e.g., tuberculosis), metabolic disorders(e.g. diabetes mellitus), etc. In these conditions, fatty liver probablyis due to migration of fat from storage deposits.

There has also been in recent years increasing interest in theformulation of "fat-free" diets in order to control obesity and/or theamount of lipids, including cholesterol, present in the blood stream asit is well known that the ingestion of fats is one means of increasingthe amount of lipids in the blood. There has been much publicity of thefact that the ingestion of fat, which essentially consists of glycerolesters of higher fatty acids which break down in the digestive tract,must be maintained at a minimum in cases where a high lipid metabolismis considered dangerous.

Despite intensive research for hypolipiodal agents, includinghypocholesterolemic agents, relatively few compounds have been foundwhich are acceptable for long-term use and even these have drawbacks.For example, natural and synthetic estrogens are known to inhibitcholesterol induced atherosclerosis in mammals. In general, however, theundesirable feminizing side effects of estrogens limit their usefulnessin male mammals. These side effects have stimulated a search for"non-estrogenic estrogens" (compounds in which the sterolic effect hasbeen separated from the estrogenic effect) but to date no useful agenthas been discovered. Other hypocholesterolemic agents have met withvarying degrees of success but undesirable side effects have beenencountered. In addition, the use of a fat-free diet to alter thelipiodal metabolism has obvious limitations because fat is usedextensively in the preparation of many foods and hence such a diet isextemely difficult to maintain.

It has now been unexpectedly discovered that the oral administration ina solid pharmaceutical formulation of a composition having a molecularstructure in which there is attached to a polyenic macrolide nucleushaving at least five conjugated double bonds, at least one hydroxylgroup (i.e., a specific known polyenic macrolide antifungal antibioticcompound or a polyenic macrolide compound having at least one hydroxylsubstituent and other substituents defined hereinafter) will beeffective in altering lipid metabolism, including reducing and/orcontrolling triglycerides, cholesterol, lipoproteins, etc. in mammals,thereby providing an agent useful for the treatment of those conditionsbelieved associated with the lipid metabolism, e.g.,hypercholesterolemia and other conditions mentioned heretofore. Thisdiscovery is particularly surprising because it has been suggested inthe prior art that "Mycostatin" (trademark for nystatin), a polyenicmacrolide compound having four conjugated double bonds is ineffective onthe serum cholesterol (Steiner et al., Circulation Vol. 24, pp 729-735(1961)).

The action of the compounds of this invention is believed not due to theantibiotic function of the polyenic macrolide compounds which have beenpreviously described in the art, but apparently to their chemicalstructure.

Accordingly, one aspect of the present invention is to provide a methodfor altering lipid metabolism which comprises orally administering aneffective dose of candimycin.

Another aspect of the present invention is to provide an orallyadministered composition for altering lipid metabolism which compositioncomprises a solid pharmaceutical formulation comprising an effectivedose of a candimycin.

An additional aspect of the present invention is to provide an enterictablet or capsule containing an effective dose of a composition of thepresent invention for altering the lipid metabolism.

Other aspects of the invention will be apparent from the followingdetailed description.

As used herein, the reduction of sterol levels is intended to includethe treatment of hypersterolemia, e.g., hypercholesterolemia, as well asconditions believed associated directly or indirectly withhypersterolemia.

According to the present invention, the compositions found effective foraltering lipid metabolism in mammals comprise a molecular structure inwhich there is attached to a polyenic macrolide nucleus having at leastfive conjugated double bonds, at least one hydroxyl moiety (i.e., thewell known polyenic macrolid antifungal antibiotic compounds or acomposition having a molecular structure in which there is attached to apolyenic macrolide nucleus at least one hydroxyl group and at least onemoiety selected from the group consisting of amino sugars and N-acylderivatives thereof, aromatic amines and N-acyl derivatives thereof,carboxyls, hydroxy aliphatics, carbonyls, methyls, aliphatics andepoxies).

Since the polyenic compounds were first discovered in 1950, a large bodyof literature has become available describing the extensive chemicalinvestigation of these compounds and demonstrating that they possessgenerally similar chemical properties. The present broad classificationof the polyenic macrolide compounds is due to the work of Oroshnik etal., in 1955 (see Polyene Antibiotics, Science, Vol. 121, pp. 147-149).In 1955 only nine polyenic macrolide compounds had been isolated inreasonably pure form but since then well over fifty polyenic macrolidecompounds have been reported. Undoubtedly some of these polyenes havebeen reported more than once under different names.

The known polyenic macrolide compounds have been produced as antibioticsby cultivation of Streptomyces in different media and by extraction ofthe substances from these cultures. It has been demonstrated in theliterature that the known polyenic compounds are (1) of fairly highmolecular weight (ca 700-1400), (2) contain macrocylic lactones, betterknown as macrolides (hereinafter referred to as "plyenic macrolidecompounds"), and (3) each possess a chromophore in the nucleus of fromfour to seven conjugated double bonds (tetraenes, pentaenes, hexaenes,and heptaenes) identified by examination of their ultra-violetabsorption spectra. These conjugated systems are generally unsubstituted(except the methyl pentaenes) and either of the "all-trans" or"cis-trans" configuration. Based on the evidence available to date, itis indicated that the known polyenic macrolide compounds contain atwenty-six to a thirty-seven membered lactone ring wherein all of thering atoms except the single oxygen atom are carbons. The evidence todate also indicates that only C, H, O, and N are present in the knownpolyenic macrolide compounds.

The polyenic macrolide nucleus contains a relatively planar lipophilicsection (polyenic chromophore) and a less rigid hydrophilic section dueto the presence of highly polar substituents, particularly hydroxyls, aswell as other substituents which will be discussed in detail laterherein. All of the known polyenic macrolide compounds contain at leastone hydroxyl moiety and in some cases at least six hydroxyl moieties. Itis difficult to estimate the precise number of hydroxyl functionspresent in each known polyene macrolide compound because complete, ornearly complete structures have been proposed for relatively fewpolyenes which are: pimaricin [Cedar et al.--Acta Chem. Scand. Vol. 18,pp 72-125 (1964)]; filipin [Ceder et al.-- Acta Chem. Scand., Vol. 18,pp 558-560 (1964)]; nystatin [Birch et al.--Tetrahedron Letters, Vol.23, pp 1491-1497 (1964)]; lagosin [Dhar et al.--J. Chem. Soc., p 842(1964)]; fungichromin [Cope et al.,--J. Amer. Chem. Soc., Vol. 84, pp2170-2178 (1962).

The distinct sections of polar and non-polar character in the polyenicmacrolide nucleus result in the unique and peculiar solubilityproperties exhibited by the polyenic macrolide compounds. As a group ofcompounds the polyene macrolides generally exhibit very poor solubilityin the common organic solvents such as lower alcohols, esters, ketones,ethers, etc., and are insoluble in water. The polyenic macrolidesexhibit improved solubility in mixtures of lipophilic and hydrophilicsolvents, e.g., aqueous solutions of lower alcohols, and are easilysoluble in aqueous pyridine. Good solubility of the polyenic macrolidecompound is noted in highly polar solvents such as dimethyl sulfoxide,formamide, glacial acetic acid, etc.

Any single known polyenic macrolide compound may have substituentslinked to the ring such as amino sugars and N-acyl derivatives thereof,aromatic amines and N-acyl derivatives thereof, carboxyls, methyls,carbonyls, aliphatics, hydroxy aliphatics and epoxies. The majority ofthe polyenic macrolides are amphoteric substances. The acidity of thesepolyenes is due to a carboxyl group and the basicity of the amphotericpolyenes is due to the presence of an amino sugar known as mycosamine(3-amino 3,6 dideoxy-D-mannose) or perosamine (4-amino4,6-dideoxy-D-mannose). The basicity may also be due to the additionalpresence of aromatic amino moieties. Some polyene macrolides such asfilipin, lagosin and fungichromin are neutral. The substitution of theamine function with such organic radicals as acyl groups reduces theeffectiveness of the macrolide nucleus in altering lipid metabolism butdoes not destroy this activity. The acylation results in neutralizationof the basic properties and improved solubilities of the N-acylatedderivative in various media, such as organic solvents, and readilypermits the formation of water soluble salts, as fully described in U.S.Pat. No. 3,244,590.

The following articles should be consulted for references to thediscovery, isolation and chemical properties of the polyenic macrolidecompounds:

1. Vining, "The Polyene Antifungal Antibiotics" Hindustan AntibioticsBull., Vol. 3, pp 32-54 (1960).

2. Waksman et al., "The Actinomycetes, Vol. III, Antibiotics ofActinomycetes" (Williams and Wilkins, Baltimore, 1962).

3. Droughet, "Noveaux Antibiotiques Antifongiques" Symp. Int.Chimiotherapie, Naples, 1961, pp 21-50 (1963).

4. W. Oroshnik et al., Fortschritte der Chemie Organischer Naturstoffe"Vol. XXI, pp 18-79 (1963).

The general class of polyenic macrolide compounds to which the presentinvention is applicable are the heptaenes. These compounds will now bediscussed in greater detail by reference to the substances that fallwithin this classification.

The heptaene group of polyene macrolides are classifiable into at leastfive groups which may be correspondingly identified as follows:

A. Aromatic I--Identified as those compounds containing the heptaenemacrolide nucleus, one carboxyl group, a single amino sugar moiety(mycosamine) glycosidically linked to the macrolide nucleus and anaromatic amino moiety (p-aminophenyl) aldolically linked to themacrolide nucleus. Representatives of this group are (a) candicidinwhich may possibility be identical to trichomycin A, hamycin (minorcomponent), heptamycin, ascosin and levorin A₂ ; (b) trichomycin B whichmay possibly be identical to levorin A₃, hamycin (major component) andPA-150; and (c) levorin A.

B. Aromatic II--Identified as those compounds containing the heptaenemacrolide nucleus, one carboxyl group, an amino sugar (mycosamine)glycosidically linked to the macrolide nucleus, and an aromatic aminomoiety (N-methyl-p-aminophenyl) aldolically linked to the macrolidenucleus. Representative polyenic macrolides of this group are: (a)candimycin, and (b) hamycin (minor component of hamycin complex).

C. Aromatic III--Identified as those compounds containing the heptaenemacrolide nucleus, an aromatic amino moiety (N-methyl-p-aminophenyl),aldolically linked to the macrolide nucleus, and an amino sugar(perosamine), glycosidically linked to the macrolide nucleus. It isnoted that the aromatic amino moiety just identified has previously beenincorrectly reported in the literature as a p-aminobenzyl moiety.Representative of this group is fungimycin. This substance wasoriginally identified as antibiotic No. NC 1968 and for a brief intervalidentified as perimycin and aminomycin.

D. Non-Aromtic--Identified as those compounds containing the heptaenemacrolide nucleus, one carboxyl moiety and a single amino sugar(mycosamine), glycosidically linked to the macrolide nucleus.Representative of this group are: (a) canididin; (b) candidinin; (c)candidoin; (d) amphotericin B; (e) mycoheptin; (f) levorin B; and (g)antibiotic F-17-C.

E. Poorly Defined Heptaenes: A number of heptaene macrolide compoundshave been described in the literature but have not as yet beensufficiently characterized as to all the substituents linked to thepolyenic macrolide nucleus. These heptaene macrolides are streptomycesabikoensis heptaene, aureofacin, antibiotic 757, ayfactin A, ayfactin B,antifungin 4915, eurotin A, antibiotic AE-56, antibiotic 2814-Hgrubilin, monicamycin, antibiotics A, B, and C from Streptomyces speciesrelated to S. viridans.

It will be understood that where a polyenic macrolide compound of theclass herein described is identical with one of the above namedcompounds, but has been known by another name by reason of independentproduction or production in accompaniment to other antibiotics, theidentification of such substances by the name set forth above isintended to mean the same compound under all other designations.

The N-acyl derivatives of the polyenic macrolide compounds having fiveto seven conjugated double bonds are also useful for altering lipidmetabolism in accordance with the present invention and are generallyprepared by reaction of the corresponding acid anhydride with thepolyenic macrolide substance. In general, the acyl derivatives arederived from monocarboxylic aliphatic acids, dicarboxylic aliphaticacids and aromatic carboxylic acids. Thus the acyl derivatives and theirpharmaceutically acceptable salts, can be defined as derivatives of apolyenic macrolide compound and an organic acid, the acyl group of theacid being linked to at least one amino nitrogen of the macrolidecompound. A detailed description of the preparation of N-acylderivatives of polyenic macrolide compounds may be found, for example,in U.S. Pat. No. 3,244,590.

Examples of the various N-acyl derivatives are formyl, acetyl,propionyl, chloroacetyl (and other halogen--substituted aliphaticmonocarboxylic acids), phenylacetyl, phenoxyacetyl, butyryl, valeryl,caproyl, succinyl, phthalyl, 3-nitrophthalyl, benzoyl, substitutedbenzoyl and the like.

The pharmaceutical compositions are formulated so as to be suitable fororal administration. The active ingredient is contained in a capsule ortablet, preferably in enteric form. The quantity of effective dosesupplied by each capsule or tablet is relatively unimportant since thetotal dosage can be reached by administration of either one or aplurality of capsules of tablets or both. The capsules employed maycomprise any well known pharmaceutically acceptable material such asgelatin, cellulose derivatives, etc. The tablets may be formulated inaccordance with conventional procedure employing solid carriers,lubricants, etc., well known in the art. Examples of solid carriers are:starch, sugar, bentonite and other commonly used carriers.

The following examples illustrate suitable pharmaceutical formulationscontaining the compounds of this invention.

EXAMPLE 1

Hard gelatin capsule available from the Robin Pharmacal Corporation(size 00) is filled with about 0.83 grams of lactose (Fast Flowavailable from Foremost Daries, Inc.) and about 100 mg. of activematerial, the lactose and active ingredient being triturated together ina pestle and mortar until a very fine yellow amorphous powder resulted,prior to filling of the capsule. Obviously, any desired number ofcapsules may be filled by mixing together any amount of lactose andactive ingredient in the same weight ratio indicated above so that eachcapsule will contain 100 mg. active ingredient; and the quantity ofactive ingredient may be altered, as desired, by varying the weightratio of the indicated materials.

EXAMPLE 2

125 g. of corn starch and 2112.5 g. lactose are dried at 140° F. for 12hours before compounding. After drying, each of these materials issifted through a No. 14 mesh stainless steel screen. The sifted cornstarch and lactose are thoroughly mixed for 30 minutes and to thismixture there is added a blended mixture of 250 g. active ingredient and12.5 g. magnesium stearate. This admixture is blended and thencompressed on a tableting machine into 5000 substantially round tabletseach containing 50 mg. active ingredient and weighing about 500 mg.

EXAMPLE 3

Enteric tablets for use in this invention may be formulated as follows:

16 g. of powdered corn starch (U.S.P. quality) is dried at 120° F. for12 hours and passed through a No. 25 mesh stainless steel screen. Theshifted corn starch is then mixed with 255 g. of anhydrous lactose(direct tablet grade). To this mixture, 4 g. of magnesium stearate isadded followed by 50 g. of the active ingredient. These materials arethen mixed in a small pebble mill for 30 minutes and compressed on asingle punch machine producing 1,000 tablets, each containing 50 mg.active ingredient. Each tablet weighs approximately 325 mg. The averagehardness is 6, as measured on a Monsanto Hardness Tester.

The tablets are then placed in a coating pan rotating at 29 r.p.m. andsubjected to warm air of approximately 80° F. for about 10 minutes. Then30 cc's of a pharmaceutical glazed composition is applied, thiscomposition being refined wax and rosin free orange flake shellac withanhydrous alcohol as the medium therefor. Talcum (U.S.P.) or similardusting powder is applied to the tablets to prevent the tablets fromsticking to each other or to the pan and this procedure is followedafter the application of each coat to the tablet. The coat is allowed todry for approximately one hour. Thereafter three additional coats areapplied in a similar manner, each coat comprising 30 cc's of thepharmaceutical glaze, with approximately one hour of drying time betweenthe application of successive coats. After four coats are applied thetablets are dried overnight at room temperature and then four more coatsare applied in the same manner using the same composition. Each coat isallowed to air dry for 3 hours before applying the next coat. Each ofthe 8 coats of the enteric tablets is approximately 0.001 inch inthickness. Obviously, the thickness of the coating can be controlled byvarying the concentration of the pharmaceutical glaze in the alcoholmedium. U.S.P.

The enteric tablets are treated in accordance with the in vitrodisintegration test for enteric-coated tablets described in U.S. P. XVIIand were found to pass this test.

While the number of coats used in the example heretofore described is 8,it will be appreciated that there are many factors to be consideredwhich permit variation in the number of coats, including the size andshape of the tablets or capsules, the type of coat or combination ofcoats, etc.

Other procedures and materials well known in the prior art may beemployed to prepared suitable enteric coatings. The selection of thecoating substance is governed to a large extent by pH and enzymeconsiderations and the desire to have the enteric compositiondisintegrate or dissolve when it reaches the duodenum region of theintestinal tract and not in the stomach. The disintegration ordissolution of an enteric coating in the intestinal tract usuallydepends on several factors, the most important of which are (1) thepresence of acidic groups in the enteric substance which cause it to beinsoluble in the low pH environment of the stomach but soluble in theintestinal tract due to the higher (but usually not alkali) pH of themedia there, and (2) the resistance of the coating to attack by oral andgastric enzymes.

Illustrative of other well substances that may be used for the entericcoating are the following: cellulose acetate phthalate with resinouscarrier; cellulose acetate phthalate-tolu balsam-shellac; celluloseacetate phthalate with fats and waxes; shellac-castor oil; ammoniatedshellac; shellac-stearic acid-tolubalsam; stearic acid-castor oil overshellac-silica gel, cellulose acetate phthalates with or withoutplasticizer and dusting powder(s); acid phthalates of glucose, fructose,etc; ternary copolymers of styrene, methacrylic acid and butylhalf-ester of maleic acid; alkyd resin-unsaturated fatty acids-shellac;polyvinyl acid phthalate, etc.

For a description of the procedure for manufacturing entericformulations such as those exemplified heretofore, reference should bemade to U.S. Pat. Nos. 2,196,768; 2,433,244; 2,455,790; 2,540,979;2,858,252; 3,080,346 and British Pat. Nos. 760,403 and 820,495.

The effectiveness of the compounds of this invention has been indicatedby tests in large mammals, i.e., those weighing at least about 1kilogram. For example, tests conducted on dogs with candicidindemonstrates the effectiveness of the polyenic macrolide compoundsincluding the reduction of blood cholesterol levels.

The basic procedure used for determination of cholesterol levels is themethod of J. P. Peters and D. D. Van Slyke, described in the text"Quantitive Clinical Chem." Vol. II, pp. 504-508 (Williams & Wilkins).

Average control serum lipid levels are established prior to theadministration of the candicidin to the dogs which are stabilized ondiet, feeding regime. After the average control serum lipid values areobtained, 20 mg/kg of body weight is orally administered twice daily,once in the morning and the second dose about 6 to 8 hours later, eachdose containing 10 mg of active ingredient. After two weeks of oraladministration, blood samples are tested for serum cholesterol. Allblood samples are drawn for assay prior to feeding with no food (exceptwater) for at least 12 hours. Administration of candicidin is continuedand blood samples are tested again for serum cholesterol at the end ofeach week of administration.

While the present invention is not predicated on any present theoreticalconsiderations, it is believed that the possible mechanism by which thecompositions of this invention exhibit their action is through theformation of a complex in the intestinal tract with sterols, such ascholesterol, thus preventing absorption of the complexed sterol.Therefore, absorption of the compositions of this invention is notnecessary for alteration of the lipid metabolism to occur. Initially,depleting the absorption of the sterols is likely to stimulate a releaseof stored materials from the tissues (fatty acids, triglycerides,sterols, etc.) which in some instances may result in an initial increasein serum levels which will then be followed by a decrease afterequilibration is reached.

There are indications that the larger the chromophore in the macrolidenucleus the more effective is the compound in altering lipid metabolisme.g., reducing blood cholesterol levels. Therefore commensurate with thedesideratum of obtaining the highest degree of effectiveness of thecompositions of this invention, it is preferred to use the heptaenemacrolide compounds.

It is also indicated that cleavage or other alteration of the macrolidenucleus which opens the lactone ring will destroy the activity of thecompounds as will alteration of the chromophore present in the nucleusby total hydrogenation.

Since no one of the substituents found in the polyenic macrolidecompounds such as amino sugars, aromatic amines, carboxyls, carbonyls,methyls, aliphatics, epoxies, etc., occur in all of the polyenicmacrolide compounds described herein, indications are that thesesubstituents, except for the hydroxyl function, are not essential foraltering lipid metabolism, but rather that the active structure is themacrolide ring containing a conjugated chromophore portion (lipophilicsection) and the flexible hydrophilic portion.

It is preferred, commensurate with the desideratum of obtaining thehighest degree of effectiveness of the compositions of this inventionper given dose of active ingredient, to use an enteric tablet orcapsule. Thus when using a specific known polyene macrolide compound inthe form of an enteric solid, the entire compound will remain intactwhen it reaches the intestinal tract so long as the enteric coatingcomposition retains its integrity in the stomach. On the other hand,administration of the same dose in a standard solid pharmaceuticalformulation may result in a cleavage of any amino sugar present, or ofother groups similarly sensitive to gastric conditions. Such cleavagemay further result in alteration of the polyenic macrolide nucleus,thereby diminishing the effectiveness of the active ingredient.

The effective dosage of the compounds of this invention depends upon theseverity of condition, the stage and the individual characteristics ofeach mammal being treated. It is expected that the compositions willgenerally be administered in a dosage range from about 1 mg to about 100mg active ingredient per kg of body weight per day and preferably fromabout 5 mg to about 40 mg per kg of body weight per day.

The compositions of this invention may in addition contain dietarysupplements such as vitamins, choline, salts of glycerophosphoric acidand inositol, which are known to be effective in reducing serumcholesterol levels.

What is claimed is:
 1. A process for treating hypercholesterolemia in alarge mammal in need of said treatment which comprises orallyadministering an effective dose for treating hypercholesterolemia ofcandimycin to said mammal.
 2. The process of treatinghypercholesterolemia as recited in claim 1 wherein said effective dosecomprises from about 1 milligram to about 100 milligrams of candimycinper kilogram of body weight per day.
 3. The process of treatinghypercholesterolemia as recited in claim 2 wherein said effective dosecomprises from about 5 milligrams to about 40 milligrams of candimycinper kilogram of body weight per day.